Basic esters of 1-aryl-cycloalkyl-1-carboxylic acids and a process for their manufacture



Patented July 23, 1946 7 CARBOXYLIC ACIDS AND A PROCESS FOR. THEIR MANUFACTURE Henry Martin and Franz Hiifligcr, Basel, Switzerland, assignors to J. R. Geigy A. G., Basel, Switzerland, a Swiss firm N Drawing. Application June 2, 1944,"Serial No. 538,542. In Switzerland December 16, 1942 a 1 I The present application is part of our copending application Ser. 760, filed October 18,1943.

Therapeutically valuable compounds selected nitrogenatom or also reactive esters of the amino alcohols in question are allowed to react, if necessary in the presence of acid binding agents,

. with the aforementioned acids or' salts thereof re-" spectively; jAmong the l-aryL-cycLoaIkyl-Lcarboxylic acids "there may be'understood the corresponding unsubstituted and substituted compounds of the benzene series. As essential substituents may. be mentioned: alkyl groups, while especially esters with hydrogen halide acids, with aryl sulfonic acids and the like may be used as reactive esters of amino alcohols. Moreover, it is'also possible to'jc'onyert l-aryl-cycloalkyl-lcarboxylic acid into the halogen alkyl esters and to cause the same to interact with secondary amines. The production of the halogen alkyl esters is preferably carried out by causing alkylene halogen hydrines to react with l-aryl-cycloalkyl-l-carboxylic acids or their halides, esters or anhydrides in the presence or absence of condensation agents or by causing alkylene halogen hydrines Or alkylene dihalides to react with salts of these acids and replacing by halogen the hydroxy groups which possibly may be present in the obtained compounds.

By addition of alkyl halides, alkylene halides, aryl sulfonic acid esters, dialkylsulfates, aralkyl halides and so on the quaternary compounds of the above esters are obtained in the usual manner. If, for the conversion of the cycloalkylcarboxylic acid halogen .hydrineesters, tertiary a continuation-111-; No. 506,-

4 Claims. (01. zed-469) corresponding products. described in the literature. i The present invention may be illustrated, but

not limited, by the following examples, the parts being by weight, unless otherwise stated.

' Example 1 20.8 parts of 1-phenylrcyclopenty1-bcarboxylic acid chloride, obtained from the acid (of. Am. Soc. 1934, 56, 715) by meansof thionyl chlo ride, are dissolved in 250 parts by volume of absolute ether, then, while stirring and cooling with a, mixture of common salt and ice a solution of 12 parts ofdiethyl amino ethanol. in 50 parts by volume .of absolute ether is allowed to drop thereintdfthe temperature being maintained below 0'C., whereupon stirring is continued during 2 hours at room temperature. Now, the whole is twice "shakenJout with water and once with diluted hydrochloric acid, the combined aqueous solutions are made alkaline with a potassium 1- (2 methylphenyl) -cyclopentyl- 1 -carboxylic acid-diethylaminoethanol-ester B. P.0.o5 mm; 119- 120 C. and'therefrom the hydrochloride of the melting point of 173-174 C., V 1

1- (3' 1 methylphenyl) -cyclopentyl-l-carboxylic acid-diethylaminoethanol-ester B. P.o.0a 117- 119 C. and therefrom the hydrochloride melting at 148-149 C. and

1- (4'- methylphenyl) -cyclopenty1- l-carboxylic acid-diethylaminoethanol-ester B. P.'o.o3 mm. 113-- 115 C. and therefrom thehydrochloride melting at 1679-168 6.

Emmplez I -1 20.4 parts of l-phenyl-cyclohexyl-l-carboxylic amines like trimethyl amine or triethylamine are acid (Am. Soc. 1934, 56, 715) are heated for 24 used, the quaternary ammonium compounds are directly obtained.

The l-aryl-cycloalkylelcarboxylic acidsare mostly known; the compounds not known'hithhours to boiling, while stirring, with 14' parts of 9-chloroethyl-diethyla'mirie and 20 parts of potassium carbonate in 250 parts by volumeoffdry H acetic ester. After cooling'the potassium'chloerto can be produced in the same manner as the ride is filtered ofi by suction, the residue washed recrystallised from 3 with acetic ester and the combined acetic ester solutions are extracted by means of diluted hy-.

' drochloric acid. The acid solution thus obtained is first shaken outwith ether, then the base is made freeby means of potassium carbonate solution and taken up in ethr. After having dried the ethereal solution the solvent is distilled 01f. The residue boils at l36-138 C. and a pressure of 0.12 mm. By introducing hydrochloric' acid gas into an ethereal solution of the base the hydrochloride melting at 162 C. is obtained (when absolute alcohol-l-acetic ester) ethanol ester of the acid. 7

I Erample 3 Y H 23.7 parts or 1-(3;4'-dimethylphenyl) -cyc1opentyl-l-carboxylic acid chloride are interacted according to Example 1 with 12 parts of diethyl amino ethanol; The base so-obtained boils at 0.05 mm. pressure at 126-128 C. 'When working in the same manner, but'using 23.7 parts of 1" (4' methylphenyl)-cyclohexyl-l-carboxylic acid chloride and '12 parts of diethyl amino ethanol, a base having the boiling point of 1389-140 C. at 0.08 mm. pressure is obtained. The base made according to Example 1 from 23.7 parts of l-phenyl-2z5 dimethyl-cyclopentyll -ca'rboxylic acid chloride and 12 parts of diethyl amino ethanol boils at l28-130 C. atla' pressure of 0.06 mm.

Very similar compounds'are obtained when diethyl amino ethanol is replaced by 1-dimethylamino-3-propanol.

' Example 4 tion, the mixture is shaken with ether and water' and, after the evaporation of the solvent from the ethereal solution, the l-phenyl-cyclohexyl-l carboxylic acid piperidine ethyl ester is obtained in form of a bright oil being well soluble in acids. In high vacuo it boils under a pressure of 0.1 mm. at 155-160 C.

Example 5' I V 20.8 parts of l-phenyl-cyclopentyl-l-carboxylic acid'chloride are dissolved in 200 parts of absolute benzene. While stirring and cooling, a solution of 11 parts of 'y-dimethylaminopropanol in 50parts of absolute benzene is caused to drop thereinto and the whole is subsequently heated to boiling, for 1 hour. The mixture is twice shakenwith water and once with dilute hydrochloric; acid. The collected aqueous solutions are extracted with ether,'the base freed by means of potassium carbonateand taken up "in ether.

The ethereal solution is washed with water, dried &

over potassium carbonate and the solvent is distilled off. I

The 1-plrenyl-cyclopentyl-l-carboxylic acidy-dimethylaminopropanol ester boils at 0.25 mm. 5 pressure at 125-127 C. Therefrom may be obtained the hydrochloride melting at 147-148 C. '7 In the same manner the following esters can be. produced from the corresponding acid chlorides: 1

1 (2"-methylp henyl) -cyclopentyl-l-carboxylic acid-'y-dimethylaminopropanol ester, B. P.c.oa mm. '119. -l21.C and therefrom the hydrochloride -me1ting .at1..l35.-,136' C.,

' 1- '(3'-methylphenyl) -cyclopentyl-l-carboxylic .11?- .acid-v diamethylaminopropanol ester, B. P.c.09

1'17j--l20 C, and therefrom the hydrochloride melting at 135- 136 C.

1-- '(4-methylphenyl) -cyclopentyl-l-carboxylic acid-y-dimethylaminopropanol ester, B..P.o.o4 mm.

. 109-110 C., and therefrom the hydrochloride melting at 186-187- C., and K boxylic' acid-y-dimethylaminopropanol ester, 13. P.0.15 mm; l36- 137 C. and therefrom the hydrochloride of the melting point of 156-158 C.

Q Example 6 19.4 parts of l-phenyl-cyclobutyl-lcarboxylic 7 acid chloride are caused to interact with 12 parts of diethylaminoethanol in the manner indicated in Example 5. On working up l-phenyl-cyclobutyl-l-carboxylic acid diethylaminoethanol esterboiling at 108-110 C. at-0.1 mm. pressure is obtained and therefrom the hydrochloride melting at l51-152 C.

In thecsame mannerihomologues or the nuclear-substituted 1 phenylcyclobutyl-l-carboxylic acid esters respectively may be prepared; thus 7 i may be enumerated the derivatives of the 1-( 2 40 methylphenyl) -cyclobutyl-1-carboxylic acid, of the 1- (3 '-methylpheny1) -.cyclobutyl-1-carboxylic acid, of the 1 -(4'-methylphenyl) -cyclobutyl-1- carboxylic acid, etc. 7' r 5 Example 7 7 l8 parts. of l-phenyl cyclopro'pyl l-carboxylic acid chloride are caused to react according .to the indications of Example 5 with 12 parts of diethylaminoethanol. After working up one, obtains l-phenyl-cyclopropyl 1-carboxylic acid diethyl- V aminoethanol ester of the'boiling point at 0.05 mm. pressure of f105107 C. and therefrom the hydrochloride melting at 133 134 C c V Iii the same ma'n'nerthe' homologuesor nuclear-substituted l-phenylcyclopropylQl-c'arbox ylic acid esters may be prepared; thus theremay be cited the derivatives of the 1-(2' methylphen-- yl)-cyclopropyl-l-carboxylic acid, of the 1-6- methylphenyl) -cyclopropy1'-1-carboxylic acid, of

{ the 1-(4'-methylphenyl)-cyclopropyl-l-carbox ylic acid. a

Moreover, also the alkylated'cyclopropaneor Ewample v H 1 23.7 parts of 1-phenyl-cyc1oheptyl l-carboxylic acid chloride are dissolved in 300 parts by volume acids respectively may be used, such as for inof absolute ether, then, while stirring and well cooling with a freezing mixture, a solution of 12 parts of diethylaminoethanol in 50 parts by volume of absolute ether is caused to drop thereinto, the temperature being maintained below 0 C. Then the whole is further stirred for 2 hours at room temperature, shaken twice with water and once with dilute hydrochloric acid, the collected aqueous solutions are made alkaline by means of potassium carbonate and shaken with ether. The ethereal solution is washed with water, dried over potassium carbonate and the solvent is distilled ofi. The so-obtained base boils at a pressure of 0.07 mm. at 140 C.

All of the tertiary amines thus obtained can easily be quaternised by heating with diethyl sulfate, dimethyl sulfate, benzyl chloride or halogen alkyl, thus yielding the corresponding ammonium salts.

What we claim is: 1. A basic ester of the formula 3 0-0 o-o cH,) ..N(alky1) (EH01!- wherein R stands for a member selected from the group consisting of phenyl and methylphenyl, m stands for one of the integers 3, 4 and 5, and n stands for one of the integers 2 and 3.

2. The 1-phenyl-cyclopentyl-l-carboxylic acid diethylamino ethanol ester of the formula CIHI Ila- H:

being a colorless liquid boiling at 126-128 C. at 0.05 mm. pressure. a

4. The 1-(4'-methylphenyl) -cyc1ohexyl-1-carboxylic acid diethylaminoethanol ester of the for- I being a liquid boiling at 138140 C. at 0.08 mm.

HENRY FRANZ HAFLIGER. 

